PRESENTED BYS.MOHAMMED RAZEETH

INTRODUCTION Alzheimer’s disease (AD), the most

common form of age-related dementia neurodegeneration of the central

nervous system That eventually leads to a gradual

decline of cognitive function and dementia

The principal neuropathological features of AD

neurofibrillary tangleS

β-amyloid (Aβ)

NEUROFIBRILLARY TANGLES

Tau protien

Tau is a low molecular weight microtubule associated protein (MAP)

In human tau found in neurons of both the peripheral and central nervous system

MICROTUBULE

very low levels of tau expression have also been reported in glial cells

Find out by Binder et al., 1985; Cleveland et al., 1977; Couchie et al., 1992; LoPresti et al., 1995; Shin et al., 1991.

TRAFFIC SYSTEM OF THE CELL Traffic systems in the form of

cytoskeletal fibers which guide the transport of motor proteins

Two distinct fiber systems for transport

The actin microfilaments and The microtubules

Three classes of ptn involve in transport

The myosins-for the microfilament tracks

The kinesins and dyneins -for microtubule tracks

NURONS SIGNALING

FUNCTIONS OF TAU PROTIEN Intracellular vesicular transport

Organization of the actin cytoskeleton

Anchoring of phosphatases and kinases

By Buee et al., 2000;Lee et al., 2001.

Tau is best characterized for its ability to bind to

stabilize and promote the polymerization of microtubules

In Human tau encode single gene located on chromosome 17q21-22 that consists of 16 exons.

ISOFORMS Isoforms generated by alternative mRNA

splicing By Andreadis et al., 1992; Neve et al

in1986 Alternative splicing of exons (E) 2 (E2),

3(E3) and 10 (E10) It produce 6 isoforms ranging in length from 352 to 441 amino

acids

TAU

It has 3R and 4R carboxy-terminal repeats

Along with specifically identified adjacent sequences are responsible for the binding of tau to MT

(Butner and Kirschner, 1991; Gustke et al., 1994; Lee et al., 1989).

Tau is a phosphoprotein with 79 potential serine or threonine

It has (Ser/Thr) phosphorylation acceptor sites Tau phosphorylation is a normal physiological

process Which decreases tau’s binding affinity for MTs (Biernat et al., 1993; Bramblett et al., 1993;

Drechsel et al., 1992; Yoshida and Ihara, 1993)

PHOSPHORLATION SITES These phosphorylation sites can be

sub-divided into 2 groups

Residues that are phosphorylated by prolinedirected kinases

Residues that are phosphorylated by non-prolinedirected kinases

Early stages of degeneration can be detected by means of phosphorylation-sensitive antibodies

Sites occur in SP or TP motifs (7 and 10,resp.) which are preferred targets of proline-directed kinases

examples: MAPkinase, GSK-3β

tau contains 5 tyrosines (no. 18, 29, 197,310, 394)

which can be phosphorylated by Tyr-directed kinases

e.g.Y18 by the kinase fyn, Bhaskar et

al., 2005

MUTATION There are three types of mutation

reported in Tau protien

20 missense mutation 3 silent mutation 2 deletion mutation

EFFECT OF MUTATION Mutation in tau promotes tau

dysfunction and it turn leads to intracellular aggregates

There are two main pathogenic mechanisms

(i) altering the mRNA splicing of exon 10 (ii) decreasing tau-MT interactions.

TAU AGGREGATION Tau important for its abnormal behavior

in AD is the aggregation into fibers Excellent solubility which counteracts aggregation in

physiological buffers.

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